HER4 and EGFR Activate Cell Signaling in NRG1 Fusion-Driven Cancers: Implications for HER2-HER3-specific Versus Pan-HER Targeting Strategies

Authors

Hibiki Udagawa
Monique B Nilsson
Jacqulyne P Robichaux
Junqin He
Alissa Poteete
Hong Jiang
Simon Heeke
Yasir Y Elamin
Yuji Shibata
Shingo Matsumoto
Kiyotaka Yoh
Shogo Okazaki
Takashi Masuko
Igor Odintsov
Romel Somwar
Marc Ladanyi
Koichi Goto
John V Heymach

Publication Date

1-1-2024

Journal

Journal of Thoracic Oncology

Abstract

Introduction: NRG1 gene fusions are clinically actionable alterations identified in NSCLC and other tumors. Previous studies have reported that NRG1 fusions signal through HER2 and HER3 but, thus far, strategies targeting HER3 specifically or HER2-HER3 signaling have exhibited modest activity in patients with NSCLC bearing NRG1 fusions. Although NRG1 fusion proteins can bind HER4 in addition to HER3, the contribution of HER4 and other HER family members in NRG1 fusion-positive cancers is not fully understood.

Methods: We investigated the role of HER4 and EGFR-HER3 signaling in NRG1 fusion-positive cancers using Ba/F3 models engineered to express various HER family members in combination with NRG1 fusions and in vitro and in vivo models of NRG1 fusion-positive cancer.

Results: We determined that NRG1 fusions can stimulate downstream signaling and tumor cell growth through HER4, independent of other HER family members. Moreover, EGFR-HER3 signaling is also activated in cells expressing NRG1 fusions, and inhibition of these receptors is also necessary to effectively inhibit tumor cell growth. We observed that cetuximab, an anti-EGFR antibody, in combination with anti-HER2 antibodies, trastuzumab and pertuzumab, yielded a synergistic effect. Furthermore, pan-HER tyrosine kinase inhibitors were more effective than tyrosine kinase inhibitors with greater specificity for EGFR, EGFR-HER2, or HER2-HER4, although the relative degree of dependence on EGFR or HER4 signaling varied between different NRG1 fusion-positive cancers.

Conclusions: Our findings indicate that pan-HER inhibition including HER4 and EGFR blockade is more effective than selectively targeting HER3 or HER2-HER3 in NRG1 fusion-positive cancers.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, ErbB Receptors, Lung Neoplasms, Neuregulin-1, Receptor, ErbB-2, Receptor, ErbB-3, Signal Transduction, Tyrosine Kinase Inhibitors, Non–small cell lung cancer, NRG1 fusion, HER family, HER4, Tyrosine kinase inhibitor

DOI

10.1016/j.jtho.2023.08.034

PMID

37678511

PMCID

PMC11161205

PubMedCentral® Posted Date

1-1-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes